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Genetic variations can range in size from macroscopic to sub-microscopic. They can take the form of gross structural changes in chromosomes, missing or extra genetic information, or minute errors in the spelling of the genetic code. Each type of genetic change requires a different technology for detection.

Mutation

Alterations to the DNA sequence are called mutations, and are the predominant source of genetic variation. Some examples of mutations include:

A single letter (base) in the sequence is swapped for another letter

One or more letters are inserted into a sequence

One or more letters are missing from a sequence

An entire segment of a gene is missing

The presence of a genetic variant does not necessarily mean disease. Some variants are beneficial, some are harmful, and still others are neutral. For example:

Example 1: Neutral or Beneficial Mutation

Normal message: GET THE RED HAT. Mutation 1: GET THE RED CAP.

Two letters have changed, but the end product is not significantly altered. This represents a neutral change that is not likely to disrupt the resultant protein and its function. In some cases this type of change may even be beneficial, improving or enhancing the protein function.

Beneficial mutations are those that have allowed our species to acquire adaptive structures or functions during the course of evolution. These include:

Binocular vision

Opposable thumbs

Persistence of the ability to metabolize lactose into adulthood

Resistance to HIV infection in some individuals

Example 2: Deleterious Mutation

Normal message : GET THE RED HAT. Mutation 2 : GET THE RED CAT.

Only one letter has changed, but the end product is significantly altered. This represents a change in the resultant protein product of this gene, which may manifest in disease.

Harmful variants can affect the protein product in several ways:

The structure of the protein is changed such that it no longer functions properly

An inadequate amount of the product is produced, thereby compromising a specific biological process or structure

An excess of the product is produced, creating a toxic cell environment or an overactive process

The impact of a mutation also depends on the environment in which it is expressed. The same mutation can be harmful in one environment, neutral in another, and beneficial in still another. Other mutations may not become harmful to an individual unless he or she is exposed to a carcinogen, allergen, or other specific environmental agent that acts on a genetic susceptibility. The environment can also change during one's lifespan and thereby change the expression of a given gene.

Polymorphism

A **polymorphism (literally, "many forms") is a genetic variation that occurs in more than 1% of the population. Polymorphisms have been identified at every level of genetic variation; from gross changes in chromosome structure, to copy number variants (see below), to differences in a single letter in the genetic sequence. Such variations may or may not have functional significance, but they often are useful for genetic analysis. Individual variations in height, skin tone, and eye color are due to such variants. In general, common, multifactorial traits and behaviors will often be associated with polymorphisms whose functional effects are still unknown.

A **single nucleotide polymorphism (or SNP, pronounced "snip") is a base site (one letter in the genetic code) that differs among individuals in a population. Analysis of SNPs in populations (for example, comparing the frequencies of selected SNPs between persons with and without a trait of interest) can provide clues to genetic variants associated with traits. Sometimes the SNP itself is associated with the trait of interest, but often the SNP is only a marker nearby the actual causal variant. SNPs have also been used in studies of human origins and race.

Polymorphism, variant, or mutation

Genetics specialists may use different terminology to refer to the source and functional implications of genetic variants.

What is a Sequence Variant? A sequence variant is a DNA sequence that differs from the standard type (the standard type is usually referred to as the wild type).

What is a Polymorhism?

A polymorphism (literally, "many forms") is a genetic locus (position on a chromosome) where two or more alleles are found in more than 1% of a population.

What is a Mutation?

A mutation is a change in a gene that affects the phenotype. Mutations can be detrimental, i.e., causing disease or otherwise compromising the function of the individual; neutral, i.e., having no positive or negative effect on the health of the individual; or positive, i.e., providing some advantage to the individual. Note that evolution would not be possible without positive mutations.

Chromosomal variations

A variety of cellular factors can produce changes in the number and structure of chromosomes, causing attendant changes in DNA sequence, and even in the amount of DNA present in the cell. For example, Down syndrome results from the presence of an extra chromosome 21. Other disorders result from structural changes, such as the deletion, duplication, or inversion of chromosome segments. In addition, hybrid chromosomes can be formed by a process called translocation.

Copy number variation (CNV)

About 10% of human genes vary in number among individuals. A person may be born with two or more copies of the same gene on a single chromosome, or, less commonly, with genes that are missing from the chromosome altogether. Called **"copy number variants" (CNVs), these genetic differences are relatively new discoveries as a result of the Human Genome Project.

The occurrence of CNVs is not completely understood, but they may be caused by "slipping" cellular machinery during DNA replication. This could result in insertions, deletions, or duplications of large segments of DNA. Some CNVs may have no functional effect, while others affect gene expression. Some psychiatric disease, eating disorders and other traits and diseases have been linked to CNVs.

Copy number variants may be involved in neuropsychiatric conditions such as tourette syndrome, schizophrenia and autism-spectrum disorders. The ways in which CNV's contribute to these conditions are still not clear. One hypothesis is that CNVs result in over- or under- production of neurotransmitters, causing abnormal brain signaling.

Epigenetic variation

Scientists are just beginning to understand what the epigenome looks like and how it functions. Some epigenetic factors come from natural sources (such as the food we eat), or are even encoded in the DNA, and are a normal part of gene regulation. Other epigenetic factors may come from artificial sources, like medicines or pollutants. Alternatively, an environmental condition, such as chronic stress, may stimulate the body to produce its own intrinsic epigenetic factors.

Epigenetic factors may act on whole chromosomes, segments of DNA, RNA, or even proteins. In general, the epigenome affects whether these molecules are available for the transcription or translation process. We discuss the mechanisms of the epigenome further in our module on Gene-Environment Interaction.

Thus, epigenetic factors will vary from individual to individual based both on their genetic sequence and on their environmental exposures. The epigenome's sensitivity to the environment also means that it can change over time throughout an individual's life. In other words, specific genes may have different effects at different times in the lifespan. This implies a genetic malleability that was previously thought impossible. This flexibility speaks to the possibility of greater understanding of human variation, as well as potential interventions to improve health, both through environmental modifications and epigenetic therapy.